scholarly journals Reversal Effects of Antifungal Drugs on Multidrug Resistance in MDR1-Overexpressing HeLa Cells

2001 ◽  
Vol 24 (9) ◽  
pp. 1032-1036 ◽  
Author(s):  
Nami IIDA ◽  
Kohji TAKARA ◽  
Nobuko OHMOTO ◽  
Tsutomu NAKAMURA ◽  
Takashi KIMURA ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Hela Cells ◽  
Antifungal Drugs

Multifunctional QD-based co-delivery of siRNA and doxorubicin to HeLa cells for reversal of multidrug resistance and real-time tracking

Biomaterials ◽  
2012 ◽  
Vol 33 (9) ◽  
pp. 2780-2790 ◽  
Author(s):  
Jin-Ming Li ◽  
Yuan-Yuan Wang ◽  
Mei-Xia Zhao ◽  
Cai-Ping Tan ◽  
Yi-Qun Li ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Real Time ◽  
Hela Cells ◽  
Real Time Tracking

scholarly journals Rationally Designed Transmembrane Peptide Mimics of the Multidrug Transporter Protein Cdr1 Act as Antagonists to Selectively Block Drug Efflux and Chemosensitize Azole-resistant Clinical Isolates of Candida albicans

2013 ◽  
Vol 288 (23) ◽  
pp. 16775-16787 ◽  
Author(s):  
Indresh Kumar Maurya ◽  
Chaitanya Kumar Thota ◽  
Sachin Dev Verma ◽  
Jyotsna Sharma ◽  
Manpreet Kaur Rawal ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Multidrug Resistance ◽  
Fluorescent Dyes ◽  
Single Photon ◽  
Specific Interaction ◽  
Antifungal Drugs ◽  
Clinical Isolates ◽  
Drug Efflux ◽  
Peptide Mimics ◽  
Fluorescence Measurements

Drug-resistant pathogenic fungi use several families of membrane-embedded transporters to efflux antifungal drugs from the cells. The efflux pump Cdr1 (Candida drug resistance 1) belongs to the ATP-binding cassette (ABC) superfamily of transporters. Cdr1 is one of the most predominant mechanisms of multidrug resistance in azole-resistant (AR) clinical isolates of Candida albicans. Blocking drug efflux represents an attractive approach to combat the multidrug resistance of this opportunistic human pathogen. In this study, we rationally designed and synthesized transmembrane peptide mimics (TMPMs) of Cdr1 protein (Cdr1p) that correspond to each of the 12 transmembrane helices (TMHs) of the two transmembrane domains of the protein to target the primary structure of the Cdr1p. Several FITC-tagged TMPMs specifically bound to Cdr1p and blocked the efflux of entrapped fluorescent dyes from the AR (Gu5) isolate. These TMPMs did not affect the efflux of entrapped fluorescent dye from cells expressing the Cdr1p homologue Cdr2p or from cells expressing a non-ABC transporter Mdr1p. Notably, the time correlation of single photon counting fluorescence measurements confirmed the specific interaction of FITC-tagged TMPMs with their respective TMH. By using mutant variants of Cdr1p, we show that these TMPM antagonists contain the structural information necessary to target their respective TMHs of Cdr1p and specific binding sites that mediate the interactions between the mimics and its respective helix. Additionally, TMPMs that were devoid of any demonstrable hemolytic, cytotoxic, and antifungal activities chemosensitize AR clinical isolates and demonstrate synergy with drugs that further improved the therapeutic potential of fluconazole in vivo.

scholarly journals Global Screening of Genomic and Transcriptomic Factors Associated with Phenotype Differences between Multidrug-Resistant and -Susceptible Candida haemulonii Strains

mSystems ◽  
2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Hao Zhang ◽  
Yifei Niu ◽  
Jingwen Tan ◽  
Weixia Liu ◽  
Ming-an Sun ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Wall ◽  
Multidrug Resistance ◽  
Multidrug Resistant ◽  
Antifungal Drugs ◽  
Cell Wall Integrity ◽  
Close Relative ◽  
Content Type ◽  
Candida Haemulonii ◽  
Resistant Strains

ABSTRACT Candida haemulonii, a close relative of Candida auris, is an emerging pathogen which frequently shows multidrug resistance especially to triazoles, the most used antifungal drugs. The mechanisms of drug resistance in C. haemulonii, however, are largely unknown. Here, we sequenced and annotated the genomes of two reference strains from the C. haemulonii complex, compared the phenotypes, genomes, and transcriptomes of a triazole-susceptible and two triazole-resistant C. haemulonii strains, and identified triazole susceptibility, morphology, fitness, and the major genetic and gene expression differences between the strains. A multidrug efflux gene, CDR1, was recurrently found to be upregulated for expression in triazole-resistant strains. Blocking the activity of Cdr1 increased the susceptibility to triazoles strikingly. Comparative transcriptome analysis also demonstrated impaired cell wall integrity, filamentous growth, and iron homeostasis in triazole-resistant strains. Finally, we also identified a zinc-binding MHR family transcription regulator gene that mutated in triazole-resistant strains spontaneously, contributing to the changes of morphology and, possibly, cell wall integrity between the strains. The study provided important clues for future studies exploring the mechanisms of multidrug resistance and related phenotypic differences of C. haemulonii strains. IMPORTANCE A comprehensive, multi-omic survey was performed to disclose the genetic backgrounds and differences between multidrug-resistant and -susceptible C. haemulonii strains. Genes were identified with mutations or significant expression differences in multidrug-resistant compared to multidrug-susceptible strains, which were mainly involved in multidrug resistance, stress fitness, and morphology. The Cdr1-encoding gene, C. haemulonii 2486 (CH_2486), was expressed at a significantly increased level in multidrug-resistant strains. Functional inhibition experiments further implicated potential roles of CH_2486 in drug resistance. A gene spontaneously mutated in resistant strains, CH_4347, was experimentally validated to influence the morphology of spores, possibly by controlling cell wall integrity.

scholarly journals Induction of the multixenobiotic/multidrug resistance system in HeLa cells in response to imidazolium ionic liquids.

2011 ◽  
Vol 58 (2) ◽  
Author(s):  
Izabela Rusiecka ◽  
Andrzej C Składanowski
Keyword(s):  
Ionic Liquids ◽  
Multidrug Resistance ◽  
Hela Cells ◽  
Cultured Cells ◽  
Efflux Pump ◽  
Inorganic Compounds ◽  
Preventive Measure ◽  
Fold Increase ◽  
Drug Synthesis ◽  
Imidazolium Ring

The multixenobiotic/multidrug resistance (MXR/MDR) system controls transport of foreign molecules across the plasma membrane as a preventive measure before toxicity becomes apparent. The system consists of an efflux pump, ABCB1, and/or a member of the ABCC family. Ionic liquids are broadly used solvents with several unique properties such as wide liquid range, negligible vapor pressure, good thermal and chemical stability and extraordinary dissolution properties for organic and inorganic compounds. Ionic liquids containing imidazolium ring are frequently used as solvents in drug synthesis. Constitutive and induced amounts of ABCB1 and ABCC1 proteins were estimated here by Western blotting and quantified by flow cytometry in HeLa cells exposed to three homologous 1-alkyl-3-methylimidazolium and one benzyl ring substituted salts. Aliphatic substituents in position 1 of the salts caused a weak toxicity but 1-benzyl ring was strongly toxic. An 8-day long treatment with 10(-4) M 1-hexyl-3-methylimidazolium chloride resulted in an about 1.5-fold increase of ABCB1 level and over 2-fold increase of ABCC1 level. The amounts of both investigated ABC-proteins were linearly dependent on the length of the imidazolium ring side chain. Such distinctive changes of the amount of MXR/MDR proteins measured in cultured cells may be a useful marker when screening for potential toxicity of various chemicals.

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